U.S. patent application number 16/951153 was filed with the patent office on 2021-03-11 for method for administration.
The applicant listed for this patent is Hoffmann-La Roche Inc.. Invention is credited to Kellie Glenn, Brian Higgins, Gwen Nichols, Kathryn Packman.
Application Number | 20210069149 16/951153 |
Document ID | / |
Family ID | 1000005227030 |
Filed Date | 2021-03-11 |
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United States Patent
Application |
20210069149 |
Kind Code |
A1 |
Glenn; Kellie ; et
al. |
March 11, 2021 |
METHOD FOR ADMINISTRATION
Abstract
There is provided a new dosage regimen for Compound A which
maximizes anti-tumor activity while maintaining acceptable toxicity
levels.
Inventors: |
Glenn; Kellie; (Roseland,
NJ) ; Higgins; Brian; (Fresh Meadows, NY) ;
Nichols; Gwen; (New York, NY) ; Packman; Kathryn;
(Bloomfield, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hoffmann-La Roche Inc. |
Nutley |
NJ |
US |
|
|
Family ID: |
1000005227030 |
Appl. No.: |
16/951153 |
Filed: |
November 18, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16510256 |
Jul 12, 2019 |
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16951153 |
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14596747 |
Jan 14, 2015 |
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16510256 |
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13759647 |
Feb 5, 2013 |
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14596747 |
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61612429 |
Mar 19, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/40 20130101;
A61K 9/146 20130101; A61K 31/401 20130101 |
International
Class: |
A61K 31/401 20060101
A61K031/401; A61K 31/40 20060101 A61K031/40; A61K 9/14 20060101
A61K009/14 |
Claims
1. A method of treating a patient suffering form cancer, comprising
administering to said patient a pharmaceutical composition
containing as an active ingredient Compound A in an amount from
about 800 mg/day to about 3000 mg/day, daily, for up to about 7
days, followed by a rest period of up to about 21 days, said
administration starting on the first day of a 28 day treatment
cycle.
2. A method of treating a patient suffering form cancer, comprising
administering to said patient a pharmaceutical composition
containing as an active ingredient Compound A in an amount from
about 800 mg/day to about 3000 mg/day, daily, for up to about 5
days, followed by a rest period of up to about 23 days, said
administration starting on the first day of a 28 day treatment
cycle.
3. The method of claim 2 wherein Compound A is administered in an
amount from about 1000 mg/day to about 2500 mg/day.
4. The method of claim 3 wherein Compound A is administered in an
amount of from about 1250 mg/day to about 1800 mg/day.
5. The method of claim 1 wherein the treatment cycle being repeated
every 28 days for up to about 12 cycles.
6. The method of claim 1 wherein Compound A is administered twice
daily in equal doses.
7. The method of claim 1 wherein the cancer is colorectal
cancer.
8. The method of claim 1 wherein the cancer is prostate cancer.
9. The method of claim 1 wherein the cancer is lung cancer.
10. The method of claim 1 wherein the cancer is kidney cancer.
11. The method of claim 1 wherein the cancer is breast cancer.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/612,429, filed Mar. 19, 2012, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is related to improved methods of
administration of
4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-pheny-
l)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methox-
y-benzoic acid (referred to herein as Compound A) in the treatment
of cancer. In particular, the invention relates to improved methods
of administration of Compound A that provide desirable
antineoplastic effects with a tolerable level of toxicity. The
methods of the invention are characterized by administering less
frequent doses comprising relatively high concentrations of
Compound A. This protocol is expected to be safer and at least as
effective as, possibly more effective than, administering more
frequent doses at lower concentrations or larger doses at
intermittent periods.
BACKGROUND OF THE INVENTION
[0003] Compound A is an orally administered pyrrolidine that
inhibits the binding of MDM2 to p53 and is thus useful in the
treatment of cancer. It has the following chemical structure:
##STR00001##
[0004] Compound A recently entered into phase I clinical trials for
the treatment of solid tumors. See ClinicalTrials.gov, identifier
NCT01462175. This compound is disclosed in US Pub 2010/0152190 A1.
To the extent necessary, this patent publication is herein
incorporated by reference.
[0005] Applicants have discovered that Compound A is especially
effective, and best tolerated, in cancer therapy when administered
in the specific doses and pursuant to the specific protocols herein
described.
SUMMARY OF THE INVENTION
[0006] The present invention relates to a method of treating a
patient suffering with cancer, in particular colon, breast,
prostate, lung or kidney cancer or osteosarcoma, comprising
administering to the patient Compound A in an amount of from about
800 to about 3000 mg/day, or from about 1000 to about 2500 mg/day,
or from about 1250 to about 1800 mg/day, for an administration
period of up to about 7 days, preferably up to about 5 days, on
days 1-7, or preferably days 1-5, of a 28 day treatment cycle,
followed by a rest period of from about 21 to about 23 days,
preferably up to about 23 days.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 illustrates the antitumor activity, as demonstrated
by the change in mean tumor volume over time, of Compound A
monotherapy for a number of different dosing schedules, including a
continuous 5 day dosing schedule.
[0008] FIG. 2 shows the increased lifespan of mice treated with
Compound A for the different dosing schedules also reflected in
FIG. 1.
DETAILED DESCRIPTION OF THE INVENTION
[0009] "Tumor control" means that the perpendicular diameters of
measurable lesions have not increased by 25% or more from the last
measurement. See, e.g., World Health Organization ("WHO") Handbook
for Reporting Results of Cancer Treatment, Geneva (1979). The
determination of tumor control or shrinkage (also referred to as
"regression") is made by known methods. For example, by evaluation
of patient symptoms, physical examination, X-ray, MRI or CAT scan
or other commonly accepted evaluation modalities.
[0010] The present invention relates to a method of treating a
patient suffering with cancer, in particular colon, breast,
prostate or kidney cancer as well as osteo or tissue sarcoma,
comprising administering to the patient Compound A in an amount of
from about 800 to about 3000 mg/day, or from about 1000 to about
2500 mg/day, or from about 1250 to about 1800 mg/day, for an
administration period of up to about 7 days, preferably up to about
5 days, on days 1-7, or preferably days 1-5, of a 28 day treatment
cycle, followed by a rest period of from about 21 to about 23 days,
preferably up to about 23 days. The course of a preferred cycle is
about 28 days, though cycles anywhere between about 14 and about 28
days are contemplated. This treatment cycle is repeated for as long
as the tumor remains under control and the regimen is clinically
tolerated.
[0011] Dosages of Compound A can be applied either as a body
surface area ("BSA") adapted dose (mg/m.sup.2/day) or following
flat dosing (mg/day). Compound A may be administered as a single
dose daily or divided into multiple daily doses.
[0012] A patient's body measurement in square meters ("m.sup.2")
typically ranges from about 1.4 m.sup.2 to about 2.2 m.sup.2. Thus,
the total amount of Compound A to be delivered in a treatment cycle
(mg) using a BSA adapted dose would be calculated as follows:
[Dose
intensity(mg/m.sup.2/week)].times.[BSA(m.sup.2)].times.[number of
weeks in treatment cycle].
[0013] In an embodiment, Compound A is administered daily for about
5 days, on days 1-5 of a treatment cycle, followed by a rest period
of 23 days ("5+/23-"). The 5+/23- treatment schedule is expected to
be superior to interim schedules or to longer schedules as
currently on-going Phase I studies indicate that in solid tumors,
maximal apoptosis occurs only after about 48 hours of continuous
exposure and longer schedules seem to present occurrence of delayed
thrombocytopenia ("TCP"). Thus, a 3-5 daily treatment schedule is
expected to provide the best benefit ratio taking into
consideration efficacy and toxicity
[0014] Compound A is administered daily, either once or twice (bid)
daily, preferably once daily. The compound is administered to the
patient in an oral unit dosage form, most preferably in tablet
form.
[0015] Preferably, the 5 day treatment schedule is repeated every
twenty-eight days, or as soon as permitted by recovery from
toxicity, for so long as the tumor is under control or regressing
and the patient tolerates the regimen. Preferably, these treatment
cycles are repeated for a total of up to about 12 cycles.
[0016] In an embodiment, Compound A is administered daily in an
amount from about 800 to about 3000 mg/day for up to about 5 days
on days 1-5 of a 28 day cycle.
[0017] In another embodiment, Compound A is administered daily in
an amount from about 1000 to about 2500 mg/day for up to about 5
days on days 1-5 of a 28 day cycle.
[0018] In another embodiment, Compound A is administered daily in
an amount from about 1250 to about 1800 mg/day for up to about 5
days on days 1-5 of a 28 day cycle.
[0019] The present invention may be exemplified by controlled
preclinical animal studies as shown in the Examples below, which
illustrates the invention without limitation.
EXAMPLES
[0020] The superiority of the 5 day regimen of the present
invention on solid tumors is demonstrated by the following
experiments.
[0021] Abbreviations used herein are as follows:
TABLE-US-00001 x times pc orally bid twice daily wk week qd once
daily qd.times.5 once daily for five days qweekly or 1.times./wk
once a week BWL body weight loss SD standard deviation
Toxicity
[0022] In the examples below, weight loss was graphically
represented as percent change in mean group body weight, using the
formula: ((W-W.sub.0)/W.sub.0).times.100, where `W` represents mean
body weight of the treated group at a particular day, and `W.sub.0`
represents mean body weight of the same treated group at initiation
of treatment. Maximum weight loss was also represented using the
above formula, and indicated the maximum percent body weight loss
that was observed at any time during the entire experiment for a
particular group. Toxicity is defined as .gtoreq.20% of mice in a
given group demonstrating .gtoreq.20% body weight loss and/or
death.
Tumor Growth Inhibition (TGI) and Assessment of Survival/Increase
in Life Span (ILS)
[0023] Efficacy data was graphically represented as the mean tumor
volume .+-.standard error of the mean (SEM). In addition, tumor
volumes of treated groups were presented as percentages of tumor
volumes of the control groups (% T/C), using the formula:
100.times.((T-T.sub.0)/(C-C.sub.0)), where T represented mean tumor
volume of a treated group on a specific day during the experiment,
T.sub.0 represented mean tumor volume of the same treated group on
the first day of treatment; C represented mean tumor volume of a
control group on the specific day during the experiment, and
C.sub.0 represented mean tumor volume of the same treated group on
the first day of treatment.
[0024] Tumor volume (in cubic millimeters) was calculated using the
ellipsoid formula: (D.times.(d.sup.2))/2, where "D" represents the
large diameter of the tumor and "d" represents the small diameter.
In some cases, tumor regression and/or percent change in tumor
volume was calculated using the formula: ((T-T.sub.0)/
T.sub.0).times.100, where `T` represents mean tumor volume of the
treated group at a particular day, and `T.sub.0` represents mean
tumor volume of the same treated group at initiation of
treatment.
[0025] Statistical analysis was determined by the rank sum test and
One Way Anova and a post-hoc Bonferroni t-test (SigmaStat, version
2.0, Jandel Scientific, San Francisco, Calif., USA). Differences
between groups were considered to be significant when the
probability value (p) was .ltoreq.0.05.
[0026] For survival assessment, the percent of increased life space
(ILS) was calculated as: 100.times.[(median survival day of treated
group-median survival day of control group)/median survival day of
control group]. Median survival was determined utilizing Kaplan
Meier survival analysis. Survival in treated groups was
statistically compared with the vehicle group and survival
comparisons were done between groups using the log-rank test (Graph
Pad Prism, La Jolla, Calif., USA). Differences between groups were
considered significant when the probability value (p) was
.ltoreq.0.05.
EXAMPLE 1
[0027] The antitumor activity of Compound A in the human
osteosarcoma cancer xenograft model SJASA1 in immunocompromized
mice using a variety of different schedules was assessed.
A. Test Compound A
[0028] Compound A was formulated as an amorphous solid dispersion
micro-bulk precipitate (MBP) powder containing 30% drag substance
and 70% HPMC-AS polymer was reconstituted immediately before
administration as a suspension in Klucel/Tween, and remaining
suspension was discarded after dosing. All dose levels are reported
as the actual dosage of Compound A rather than including drug plus
polymer.
B: In Vivo Assays
Animals
[0029] Female athymic Crl:NU.about.Foxn1nu mice (10/group),
obtained from Charles River Laboratories (Wilmington, Del.) were
utilized when they were approximately 10-12 weeks of age and
weighed 23-25 g. The health of the mice was assessed daily by gross
observation and analyses of blood samples taken from sentinel
animals housed on shared shelf racks. All animals were allowed to
acclimate and recover from any shipping-related stress for a
minimum of 72 hours prior to experimental use. Autoclaved water and
irradiated food (5058-ms Pico Lab mouse chow, Purina Mills,
Richmond, Ind.) were provided ad libitum, and the animals were
maintained on a 12 hour light and dark cycle. Cages, bedding and
water bottles were autoclaved before use and changed weekly. All
animal experiments were conducted in accordance with the Guide for
the Care and Use of Laboratory Animals, local regulations, and
protocols approved by the Roche Animal Care and Use Committee in an
AAALAC accredited facility.
Tumors
[0030] SJSA cells (ATCC) were maintained in RPMI 1640+10% (v/v)
heat-inactivated PBS+1% (v/v) 200 nM L-glutamine. Each mouse
received 5.times.10.sup.6 cells in a 1:1 mixture of phosphate
buffered saline and Matrigel in a total volume of 0.2 ml. Cells
were implanted subcutaneously in the right flank using a 1 cc
syringe and a 26 gauge needle.
Study Design:
[0031] The doses selected for Compound A and schedules utilized in
this study are shown in Table 1 below.
TABLE-US-00002 TABLE 1 Study Design Tumor Model Treatment Groups
SJSA 1. Vehicle qd po 2. Compound A 7.5 mg/kg qd po 3. Compound A
15 mg/kg qd po 4. Compound A 30 mg/kg qd po 5. Compound A 20 mg/kg
20 days qd po, 8 days off 6. Compound A 50 mg/kg 1.times./week po
7. Compound A 100 mg/kg 1.times./week po 8. Compound A 200 mg/kg
(given as two 100 mg/kg doses 8 hours apart (bid)), 1.times./week
pa 9. Compound A 50 mg/kg 4 days qd po, 10 days off .times. 2
cycles 10. Compound A 50 mg/kg 2 days qd po, 5 days off .times. 4
cycles 11. Compound A 100 mg/kg 2 days qd po, 5 days off .times. 4
cycles 12. Compound A 80 mg/kg 5 days qd po, 23 days off 13.
Compound A 100 mg/kg 2 days qd po, 12 days off .times. 2 cycles
Treatment
[0032] Compound A was administered orally (po) using a 1 cc syringe
and 18-gauge gavage needle (0.2 ml/animal). Treatment duration was
2-4 weeks. Dates of tumor implant, treatment initiation (study
start date), and termination of treatment (study end date) can be
found in Table 6 below. The starting tumor volume for this study
was about 220 mm.sup.3. Tumor volumes and animal body weights were
measured three times per week and animals were monitored for
clinical signs daily.
[0033] The results of this experiment are summarized Tables 1-3
below and FIGS. 1 and 2. As can be seen, the 5 day treatment
schedule yielded the greatest per cent increase in life span (%
ILS) as well as high per cent tumor growth inhibition (% TGI) with
reasonable toxicity. FIG. 1 also shows good growth inhibitory
activity of the 5 day on/23 day off treatment schedule.
TABLE-US-00003 TABLE 2 % Change in Body Weight at end of Maximum %
Maximum % # of animals Group Frequency Study Day 29 Weight loss
Weight gain .gtoreq.20% BWL Mortality Vehicle QD 13.0 -1.2 13.0 0 0
Compound A 1.times./wk 9.1 4.2 9.1 0 0 100 mg/kg Compound A
1.times./wk 6.3 1.9 6.3 0 0 200 mg/kg (Two 100 mg/kg doses 8 hr
apart Compound A 2 on/5 off .times. 4, QD 7.1 -0.8 7.1 0 0 50 mg/kg
Compound A 5 on/23 off, QD 8.0 0.3 8.0 0 0 80 mg/kg Compound A 20
on/8 off, QD 1.2 -3.9 1.2 0 0 20 mg/kg Compound A 2 on/12 off
.times. 2, QD 0.9 -0.6 1.8 0 0 100 mg/kg Compound A 4 on/10 off
.times. 2, QD 1.2 -1.1 1.2 0 0 50 mg/kg Compound A QD 5.9 -2.2 5.9
0 0 15 mg/kg Compound A 2 on /5 off .times. 4, QD 1.3 -2.8 1.3 0 0
100 mg/kg Compound A QD 1.3 -0.2 1.3 0 0 30 mg/kg Compound A
1.times./wk 6.6 -0.3 6.6 0 0 50 mg/kg Compound A QD 9.0 -0.3 9.0 0
0 7.5 mg kg
TABLE-US-00004 TABLE 3 Efficacy Summary (left side) Group Mean
Tumor Mean Tumor Vehicle or (mm3) Start Volume (mm3) End Compound A
Frequency Study Day: 11 SEM SD Study Day: 32 SD SEM Vehicle QD
215.03 .+-.19.00 .+-.60.08 4696.49 .+-.785.28 .+-.296.91 50 mg/kg
1.times./week 275.41 .+-.22.66 .+-.71.65 22.66 .+-.1103.00
.+-.348.80 7.5 mg/kg QD 240.88 .+-.18.01 .+-.56.95 18.01 .+-.956.45
.+-.302.46 100 mg/kg 1.times./week 193.61 .+-.9.67 .+-.30.57 474.73
.+-.273.78 .+-.86.58 15 mg/kg QD 232.37 .+-.16.42 .+-.51.93 16.42
.+-.872.83 .+-.276.01 50 mg/kg 2 on/5 off .times. 4, QD 203.43
.+-.18.78 .+-.59.39 257.29 .+-.102.12 .+-.32.29 80 mg/kg 5 on/23
off, QD 197.38 .+-.12.80 .+-.40.48 128.05 .+-.84.89 .+-.26.84 20
mg/kg 20 on/8 off, QD 207.20 .+-.16.97 .+-.53.67 315.19 .+-.277.51
.+-.87.76 100 mg/kg 2 on/12 off .times. 2, QD 201.40 .+-.9.86
.+-.31.18 179.88 .+-.154.02 .+-.48.71 50 mg/kg 4 on/10 off .times.
2, QD 213.61 .+-.12.09 .+-.38.23 244.70 .+-.240.07 .+-.75.92 100
mg/kg 2 on/5 off .times. 4, QD 190.78 .+-.25.68 .+-.81.22 25.68
.+-.15.82 .+-.5.00 30 mg/kg QD 250.86 .+-.19.35 .+-.61.19 19.35
.+-.159.01 .+-.50.28 100 mg/kg 200 mg/kg 224.88 .+-.12.02 .+-.38.02
158.95 .+-.68.86 .+-.21.78 (Two 100 mg/kg doses, 8 hr apart)
.times. 1.times.
TABLE-US-00005 TABLE 4 Survival Summary 50% 50% Treatment Vehicle %
p Group Days days ILS value Vehicle QD -- -- -- -- Compound A
1.times./wk 46 26 77 <0.0001 100 mg/kg Compound A Two 100 68 26
162 <0.0001 200 mg/kg mg/kg doses, 8 hr apart 1.times./wk
Compound A 2 on/5 off .times. 57 26 119 <0.0001 50 mg/kg 4, QD
Compound A 5 on/23 59 26 127 <0.0001 80 mg/kg off, QD Compound A
20 on /8 46 26 77 <0.0001 20 mg/kg off, QD Compound A 2 on/12
off .times. 57 26 119 <0.0001 100 mg/kg 2, QD Compound A 4 on/10
55 26 112 <0.0001 50 mg/kg off .times. 2, QD Compound A QD 42 26
62 <0.0001 15 mg/kg Compound A 2 on/5 off .times. 75 26 188
<0.0001 100 mg/kg 4, QD Compound A QD 59 26 127 <0.0001 30
mg/kg Compound A 1.times./wk 32 26 23 0.0036 50 mg/kg Compound A QD
32 26 23 0.0012 7.5 mg/kg
[0034] Overall, the 5 days on and 23 days off (5+/23-) schedule is
predicted to reduce MDM2 inhibitor-induced thrombocytopenia in
humans undergoing treatment for solid tumors, while still
maintaining antitumor efficacy, as compared to other regimens
considered.
* * * * *